Recruiting ENT and Audiology patients into pharmaceutical trials: evaluating the multi-centre experience in the UK and USA

Figures & data

Table 1. Eligibility criteria that were specific to QUIET-1, including a history of approved substantial changes to the Clinical Trial Protocol.

QUIET-1 specific inclusion criteria (version 1.5, 9 July 2015)	History of substantial changes to the protocol
Females of child-bearing potential must have a negative pregnancy test at screening and baseline visits and practice two reliable methods of contraception throughout the study.	V1.1 (14 Aug 2014) amended to ensure that women use two methods of contraception.
Pure Tone Average (for frequencies at 0.5, 1, 2 and 4 kHz) ≤ 60 dB hearing level (HL), across the two ears.	V1.3 (13 Nov 2014) amended to include 20 and 60 dB HL in the Pure Tone Average calculation.V1.4 (9 Feb 2015) requirement for Pure Tone Average ≥20 dB removed.
Sensorineural hearing loss defined by any single audiometric threshold estimate >20 dB for frequencies at 0.5, 1, 2, 4, 6 and 8 kHz.	V1.4 (9 Feb 2015) individual frequency thresholds >20 dB instead of lower Pure Tone Average ≥20 dB.
Duration of tinnitus ≥6 and ≤18 months at enrolment.
English speaking male or female.
≥18 y of age.
UK residents, registered with a UK General Practitioner.
Stable tinnitus (consistent from day to day).
Score ≥24 and ≤68 on the Tinnitus Functional Index (TFI; Meikle et al. 2012).
If a hearing aid or sound generator user then confirmed consistent daily device usage over the past six months.
QUIET-1 specific exclusion criteria (version 1.5, 2 July 2015).	History of substantial changes to the protocol.
Surgical or medical condition that would be expected to significantly affect absorption of medicines.	V1.3 (9 Nov 2014) amended to include only those surgeries or medical conditions expected to affect absorption.
Any acute disabling tinnitus.
Central nervous system pathologies (such as multiple sclerosis, Parkinson’s disease etc.).
Moderate or severe depression or generalised anxiety as indicated by a score of ≥11 out of 21 on the Hospital Anxiety and Depression Scale (Zigmond and Snaith 1983).
Use of central nervous system active drugs except analgesics and those specified in the Clinical Trial Protocol.
Presence or history of relevant severe adverse reaction to any drug or a history of sensitivity to potassium channel modulators.
Tinnitus as a concomitant symptoms of a known otological condition (including but not limited to otitis externa, otitis media, otosclerosis, cholesteatoma, Ménière’s disease or other vestibular problems, acoustic neuroma or temporo-mandibular joint disorder).
Intermittent tinnitus (comes and goes from one day to the next).
Pulsatile tinnitus (rhythmical sounds that often beat in time with the heartbeat).
Severe hearing impairment such that verbal communication is unreliable.
Participation in a hearing study, involving an intervention, within three months from the last study visit.

Table 2. Eligibility criteria that were specific to CLARITY-1, including a history of approved substantial changes to the Clinical Trial Protocol.

CLARITY-1 specific inclusion criteria (version 4.3, 24 February 2016)	History of substantial changes to the protocol
Males who are sexually active must use a barrier method, unless vasectomised.
Females must be confirmed to be of non-childbearing potential.
Speech-in-noise deficit as shown to be equal or greater than 5 dB signal-to-noise ratio (SNR) on the QuickSIN test presented binaurally.
Audiology criteria: a) air conduction thresholds at 2 kHz ≤60 dB HL, b) pure tone audiometry at 0.5, 1 and 2 kHz cannot exceed 45 dB HL, c) no air conduction threshold >75 dB HL at 4 kHz in both ears, d) no greater than a 15 dB HL difference between ears and e) no recent history of middle ear disease.	Version 3.0 (22 Oct 2015) amended to relax configuration criteria removing restriction on air conduction at 0.25, 0.5 and 1 KHz ≤40 dB HL in both ears and removed restriction of air conduction threshold being less than 75 dB HL at 3 and 6 Hz.
Willing to refrain from significant non-study medication following the baseline visit.
Mother-tongue American English, male or female.
50–89 years of age.	Version 3.0 (22 Oct 2015) amended to relax age criteria from 60–89 years to 50–89 years of age.
Reporting difficulty in hearing speech in noisy environments.
CLARITY-1 specific exclusion criteria (version 4.3, 24 February 2016)	History of substantial changes to the protocol
History of sudden onset hearing loss.
Present conductive hearing loss of greater than 15 dB difference between air- and bone-conduction audiometry at two or more consecutive frequencies.
Montreal Cognitive Assessment <22.
Current hearing aid user or previous user of hearing aids ≤6 months ago (intermittent user) and ≤3 years (consistent user).
Score >30 on the TFI (Meikle et al. 2012).	Version 3.0 (22 Oct 2015) amended to relax tinnitus criteria from TFI greater than 24 to 30.
History of ototoxic medication such as cisplatin or history of dynamic cochlear pathology or chronic middle ear disease.
Currently taking or planning to take medications that are prohibited by the Clinical Trial Protocol.
Professional musician with around five years or more musical training and performance.
Any acute disabling illness.

Figure 1. Recruiting sites for QUIET-1 in England (left-hand panel) and for CLARITY-1 in the US (right-hand panel).

Table 3. Timeline for opening sites to QUIET-1 recruitment, with screening and randomisation listings.

Site number^a	Date opened for recruiting	Participants screened (n = 214)	Participants randomised to treatment (n = 91)^b	Efficiency^c (%)
03	10 October 2014	22	11	50
09	10 October 2014	12	6	50
08	17 October 2014	14	8	57
02	23 October 2014	32	14	44
04	27 October 2014	29	15	52
10	3 November 2014	13	6	46
06	6 November 2014	4	1	25
13	21 January 2015	9	4	44
12	11 February 2015	7	2	29
01^d	17 February 2015	28	7	25
17	23 April 2015	6	3	50
18	14 May 2015	14	6	43
14	22 June 2015	2	0	0
15	22 June 2015	10	4	40
19	28 July 2015	12	4	33

^aThree sites were opened, but not listed because they did not screen any participants before the trial was terminated.

^bIt should be noted that a “per protocol” population is not available and that a proportion of those randomised were not per protocol.

^c Efficiency of recruitment at each site refers to the number of participants randomised as a percentage of those screened.

^d The Academic Partner was at site 01.

Table 4. Timeline for opening sites to CLARITY-1 recruitment, with screening and randomisation listings.

Site number	Date opened to recruiting	Participants screened (n = 277)	Participants randomised to treatment (n = 78)^a	Efficiency^b (%)
01^c	5 March 2015	45	11	24
04	5 March 2015	38	23	64^d
12	18 May 2015	10	3	30
13	26 May 2015	19	7	37
14	26 May 2015	16	2	13
15	9 June 2015	22	2	9
18	13 July 2015	21	2	10
05	15 August 2015	8	4	50
08	11 September 2015	1	0	0
11	9 September 2015	32	4	13
17	9 September 2015	30	8	23
02	2 October 2015	6	1	0
19	12 October 2015	29	12	4

^aIt should be noted that a “per protocol” population is not available and that a proportion of those randomised were not per protocol.

^b Efficiency of recruitment at each site refers to the number of participants randomised as a percentage of those screened.

^c The Academic Partner was at site 01.

^d Denotes an inflated efficiency since the site randomised 11 participants not according to protocol who may not have met the eligibility criteria.

Table 5. Efficiency of the different recruitment methods used in the QUIET-1 and CLARITY-1 RCTs.

	QUIET-1^a					CLARITY-1^b
Recruitment method	Pre-screened	Passed pre-screening	Screened	Passed screening	U/Planned, U/Paid	Pre-screened	Passed pre-screening	Screened	Passed screening	U/Planned, U/Paid
Trial registration	0	0	0	0		3	2	2	2
Clinicaltrials.gov, centrewatch						3	2	2	2	P,U
Poster/Flyer	102	38	7	3		14	5	5	3
Supplementary file B	75	28	6	2	P,U
Supplementary file C						14	5	5	3	P,U
Community posts	27	10	1	1	U,U
Print publication	90	36	4	2		3	3	3	0
Regional magazine	7	0	0	0	P,P
Newspaper	60	25	0	0	P,U	3	3	3	0	U,P
Tabloid magazines	10	4	2	1	P,U
Community magazine	13	7	2	1	U,P
National Autifony advert						0	0	0	0	U,P
Internet	80	46	5	0		2	1	1	0
Websites, post forums	80	46	5	0	P,U
Websites, press releases						2	1	1	0	P,U
Social media	4	1	0	0		1	0	0	0
Facebook and Twitter	4	1	0	0	P,U
Facebook						1	0	0	0	U,U
Referral	57	33	5	1		60	23	23	4
Professional	11	8	3	1	P,U	8	3	3	1	P,U
Personal	46	25	2	0	U,U	52	20	20	3	P,U
Radio	21	6	1	0
Opening announcements	21	6	1	0	P,U
Database review						68	11	11	2
Clinic/Research database						68	11	11	2	P,U
Unable to code	71	30	6	2
TOTAL pre-screenings	425	190				151	45
TOTAL screening visits			28	8				45	11

^aQUIET-1 data was sourced from the Nottingham site. The number telephone pre-screened was 433, but eight of those were pending a decision at the point of study termination. Hence, number reported here is n = 425.

^b CLARITY-1 data was sourced from USF. At USF, 151 individuals were pre-screened up to the end of the study.

Each recruitment method is coded as either Unplanned (U) or Planned (P)and Unpaid (U) or Paid (P).

Figure 2. Efficiency of the different recruitment methods used in the QUIET-1 and CLARITY-1 RCTs. The top panel shows pre-screening efficiency measured by determining the number of people eligible for screening as a percentage of those who underwent telephone pre-screening. The bottom panel shows screening efficiency measured by the number of randomised participants as a percentage of those screened.

Meikle, M. B., J. A. Henry, S. E. Griest, B. J. Stewart, H. B. Abrams, R. McArdle, and P. J. Myers, et al. 2012. “The Tinnitus Functional Index: Development of a New Clinical Measure for Chronic, Intrusive Tinnitus.” Ear and Hearing 33 (2): 153–176. doi:10.1097/AUD.0b013e31822f67c0.

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Zigmond A. S. and R. P. Snaith. 1983. “The Hospital Anxiety and Depression Scale.” Acta Psychiatrica Scandinavica 67 (6):361–370. doi:10.1111/j.1600-0447.1983.tb09716.x.

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